Process for preparing a pharmaceutical formulation containing levothyroxine sodium

ABSTRACT

The invention relates to a pharmaceutical preparation comprising levothyroxine sodium, gelatin and fillers, which is free of organic solvent residues.

The invention relates to a novel stable pharmaceutical preparationcomprising levothyroxine sodium, gelatin and fillers and which is freeof organic solvent residues.

This novel preparation has an improved stability and can be used as athyroid hormone preparation.

This novel preparation furthermore has an improved release of activecompound in vitro.

The invention was based on the object of making available novelmedicaments in the form of pharmaceutical preparations, which havebetter properties than known medicaments used for the same purposes.

In the Federal Register Vol. 62, No. 15, Aug. 14, 1997; page 43535, theDepartment of Health and Human Services, Food and Drug Administration,published the facts that the products available on the U.S. market whichcomprise levothyroxine sodium and are orally administered have stabilityproblems and therefore must be present in an up to 20% excess dose andthat manufacturers must develop appropriate novel administration forms.The requirements on in-vitro release for levothyroxine Na tablets havefurthermore been increased. The monograph draft version of thePharmacopeial Forum (Pharm. Preview, 1995, 21, 1459-1461) proposes, inaddition to the valid Test 1 (phosphate buffer pH 7.4, in 80minutes>55%) to approve Test 2 (water in 45 minutes>70%).

This object was achieved by the discovery of the novel preparation.

Thyroxine-containing preparations with other additives such as glycine,a carbohydrate and an inorganic salt are disclosed in WO 97 17 951.

Another thyroxine preparation stabilized with thiosulfate is describedin DE 195 41 128.

A combination preparation comprising levothyroxine sodium and potassiumiodide is known from U.S. Pat. No. 5,635,209. Anotherthyroxine-containing formulation which contains thyroxine/cyclodextrincomplexes is described in WO 97 19 703.

In addition to levothyroxine sodium, the pharmaceutical formulationaccording to the invention can also contain liothyronine sodium.

The invention preferably relates to a pharmaceutical preparation asdescribed, characterized in that it contains 5 to 400 μg, preferably 10to 300 μg, in particular 25 to 300 μg, of levothyroxine sodium.

The invention furthermore preferably relates to a pharmaceuticalpreparation as described, characterized in that it containslevothyroxine sodium micronized with a particle size of between 5 μm and25 μm.

The invention furthermore preferably relates to a pharmaceuticalpreparation as described, characterized in that it contains fillersselected from the group consisting of lactose and/or maize starch and/ormicrocrystalline cellulose.

A particularly preferred pharmaceutical preparation is one characterizedin that it is a solid preparation in the form of tablets.

Particularly preferred embodiments contain 25, 50, 75, 100, 125, 150,175 or 200 μg of levothyroxine sodium.

The active compound(s) is/are sensitive to light, heat and oxygen. Onaccount of this known instability, the active compound is in an excessdose of up to 5% in the formulations.

The preparation according to the invention has a surprising stabilitywhen gelatin is used as a binder.

If this is replaced by another customary binder such as Methocel, evenat the start of the stability investigations, a decline in the activecompound content is detected and furthermore the sum of the by-productsis increased.

If, for example, the starting value of active compound is determined ina 100 μg batch in which gelatin has been replaced by Methocel, insteadof the 105% to be expected, only 100.48% is found.

Stability investigations show that the tablets according to theinvention which contain levothyroxine sodium are stable for at least 2years if they are stored at temperatures below 300° C.

Furthermore, the release of the active compound levothyroxine sodium issurprisingly favored if the active compound is employed in micronizedform. Levothyroxine sodium is customarily very sparingly soluble both inwater and also in ethanol. With a particle size between 5 μm and 25 μm(to 95%), however, a release of the active compound takes place in Test1 to >90% (phosphate buffer) and in Test 2 to >80% (water).

Surprisingly, the composition according to the invention can also beprepared without the use of organic solvents. If the water used in theprocess according to the invention is replaced by an organic solventsuch as, for example, methanol, a decline in the content oflevothyroxine sodium by 10% is moreover seen in test batches after 1year at a storage temperature of 25° C. and 60% rel. humidity.

Suitable fillers for the pharmaceutical preparation according to theinvention are preferably lactose, maize starch and/or microcrystallinecellulose, both as individual fillers and in combinations with oneanother. Particularly preferred pharmaceutical preparations, asdescribed, contain maize starch and lactose.

The invention also relates to a process for the production of apharmaceutical preparation comprising levothyroxine sodium andoptionally liothyronine sodium, characterized in that levothyroxinesodium and optionally liothyronine sodium, which is/are present insuspended form in aqueous gelatin solution, are sprayed onto thefiller(s) in a fluidized bed granulation, then a disintegrant andlubricant are admixed and the mixture is compressed to give tablets.

The invention further relates to a process as described, characterizedin that the disintegrant used is croscarmellose sodium and the lubricantused is magnesium stearate.

Further excipients or auxiliaries can be added, such as, for example,binding agents, antioxidants, colorants, lubricants, sweeteners and/oraromatic substances.

Preferred glidants or lubricants are, for example, talc, starch,magnesium and calcium stearate, boric acid, paraffin, cocoa butter,macrogol, leucine or sodium benzoate; magnesium stearate is veryparticularly preferred.

The following examples relate to the production and the composition ofthe pharmaceutical preparation according to the invention:

EXAMPLE 1

The following amounts are needed in order to prepare, for example, 2million tablets:

Levothyroxine 100 μg Ingredient Amount [kg] Levothyroxine sodium* 0.210Lactose monohydrate 131.80 Maize starch 50.00 Gelatin 10.00Croscarmellose sodium 7.00 Magnesium stearate 1.00 Water, purified**56.66 *A 5% excess dose of levothyroxine sodium was additionallyincluded. **The water is removed again by drying.

Preparation:

1. Gelatin is dissolved in about 90% of water at a temperature from 80to 100° C.

Levothyroxine sodium is suspended in about 10% of the water at roomtemperature.

The suspension is then added to the gelatin solution at 50° C. (±5° C.).The temperature of the suspension thus obtained (=granulation liquid) is45 to 50° C.

2. Lactose and maize starch are placed in a fluidized bed granulator.The granulation liquid is sprayed over the powder. The temperature ofthe granulation liquid is kept between 40 and 50° C. during the sprayingprocess. During the granulation, the temperature at the inlet is kept atapproximately 70° C. (±5° C.) and the temperature at the outlet is keptbetween 20 and 40° C. The spraying pressure is between 3 and 5 bar.After spraying, the granules are dried until a temperature ofapproximately 40° C. is reached at the outlet.

The dry granules are then screened (1 mm) according to known methods(=mixture a).

Croscarmellose sodium and magnesium stearate are correspondinglyscreened. The components are then mixed with one another for 10 minutestogether with mixture a in a drum mixer.

The press-ready mixture is then compressed to give tablets.

EXAMPLE 2

composition of a 100 mg (±3 mg) tablet which contains 100 μg oflevothyroxine sodium:

Levothyroxine sodium 0.100 mg Lactose monohydrate 65.90 mg Maize starch25.00 mg Gelatin 5.00 mg Croscarmellose sodium 3.50 mg Magnesiumstearate 0.50 mg 100.00 mg

levothyroxine sodium is to be present in an around 5% excess dose.

EXAMPLE 3

Composition of a 100 mg (±3 mg) tablet which contains 100 μg oflevothyroxine sodium:

Levothyroxine sodium 0.100 mg Liothyronine sodium 0.020 mg Lactosemonohydrate 65.88 mg Maize starch 25.00 mg Gelatin 5.00 mgCroscarmellose sodium 3.50 mg Magnesium stearate 0.50 mg 100.00 mg

Levothyroxine sodium is to be present in an around 5 excess dose.

What is claimed is:
 1. A process for the production of a pharmaceuticalpreparation, comprising spraying levothyroxine sodium and optionallyliothyronine sodium, in suspended form in aqueous gelatin solution, ontoa filler(s) in a fluidized bed granulation, admixing a disintegrant andlubricant and compressing the mixture to give tablets.
 2. A processaccording to claim 1, wherein the filler is lactose, maize starch ormicrocrystalline cellulose.
 3. The process according to claim 1, whereinThe disintegrant used is croscarmellose sodium and the lubricant used ismagnesium stearate.